The Sigma-1 receptor (S1R) is a 26 kDa protein found in portions of the endoplasmic reticulum (ER) of cells. In the central nervous system the highest levels of the S1R (CNS) are found in the postsynaptic portions of cholinergic postsynaptic densities (C-terminals) of spinal cord motoneurons. The primary objective of this proposal is to evaluate the role of S1R in regulating the excitability of motoneurons. We hypothesize that the S1R plays a direct role in regulating motoneuron excitability by activation of SK and/or Kv2.1 potassium channels in C-terminals, the effect of which is to increase the amplitude of the afterhyperpolarization potential (AHP) and thereby to reduce the frequency and duration of action potential firing. We hypothesize that activation of S1R can increase longevity of ALS mice by acting as a neuromodulatory brake on motoneuron hyperexcitability and thereby to decrease intracellular stress. We will accomplish the goals of this proposal through the following specific aims: Specific Aim 1: To determine whether S1R modulates motoneuron excitability (Electrophysiology) and influences the amplitude of electrical activity of the gastrocnemius muscle. (Motor activity). Specific Aim 2: To establish that activation of S1R can retard the progression of motoneuron degeneration in a mouse model of ALS (Pathology) by a) assessing survival of a new mouse model SOD1 ALS/S1R KO compared to the SOD1 ALS/S1R WT mice and b) assessing survival of the SOD1 ALS/S1R KO and the SOD1 ALS/S1R WT mice in the presence and absence of agonists of the S1R. Targeting S1R can potentially establish a new therapeutic treatment for ALS. PUBLIC HEALTH RELEVANCE: The hypothesis in this proposal is that the Sigma-1 receptor acts as a brake on neuronal excitability. With a reduction in neuronal excitability motoneurons experience less cellular damage and thereby remain functional for a longer period during the development of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease). We expect that activating the Sigma-1 receptor with specific drugs will further reduce cellular damage and lead to new treatment strategies for Lou Gehrig's disease.